Lyell shuffles the pipeline again

The last time Lyell carried out a pipeline cull, a year ago, a small acquisition provided it with fresh projects to fill the gap, and this plan appears to have just been repeated. Monday’s deal with China’s Innovative Cellular Therapeutics has been done just as Lyell jettisoned two more pipeline assets.

The deal is small, worth $40m up front plus about $33m in Lyell stock, and gives Lyell rights to GCC19CART, a multispecific, cytokine-releasing, autologous Car-T therapy that primarily hits GUCY2C. This target generated early promise at ESMO in 2023, but made little progress since, though Lyell claims that GCC19CART has generated the best data it’s ever seen in third-line or later colorectal cancer.

Of course this concerns very early results that Lyell will need to replicate in larger trials, but on the face of it the company appears to have gained rights to a promising Car-T therapy with activity in the elusive space of solid tumours.

At the same time comes the revelation that the addition of GCC19CART, now coded LYL273, will double the size of Lyell’s pipeline. The company’s only other disclosed asset is the anti-CD19 x CD20 Car-T therapy rondecabtagene autoleucel, derived from its October 2024 acquisition of the private cell therapy player ImmPACT Bio, for $30m plus about $40m in Lyell stock.

Meanwhile, another ImmPACT project, the Claudin8.2-targeting, TGF-β armoured Car-T IMPT-601, has dropped off Lyell’s pipeline, and in a recent SEC filing the company quietly disclosed the discontinuation of LYL119, an anti-ROR1 Car-T therapy. Earlier Lyell scrapped work on NY-ESO-1 and on TIL therapies.

CD19 and cytokines

Now comes Innovative Cellular Therapeutics’ LYL273, which Lyell describes as an anti-GUCY2C Car-T that also releases the cytokines IL-12, IL-6 and interferon-gamma. In fact the project is more complex, consisting of bispecific anti-GUCY2C and anti-CD19 Car-T cells, as well as monospecific Car-T cells against each of the two targets.

The point of targeting CD19, even though this is a solid tumour project, is to “jump start” T-cell activation and expansion by engaging B cells, Lyell says. An important consideration for manufacturing is that the LYL273 product can be generated from simultaneous transfection with multiple vectors.

As for the deal rationale, Lyell has cited a single-centre Chinese trial in which six of 15 colorectal cancer patients responded, with three of six responses confirmed. This followed a less promising dataset, in which five of 20 patients treated across various Chinese hospitals died. Lyell says this used an old manufacturing system, and involved centres without Car-T expertise.

After this Innovative Cellular Therapeutics ran a US phase 1 study, in which six of 12 patients responded overall, including four of six at dose level 2. Three of the responses cited appear to have been confirmed.

A note of concern is that one of the six patients at this high dose died from fungal sepsis after developing dose-limiting grade 3 diarrhoea and grade 4 colitis. Lyell stresses that since then a diarrhoea-management protocol, including prophylaxis, has been implemented. 

At ESMO in 2023 anti-GUCY2C Car-T projects from Parasol Biotech and ImmunoChina Pharmaceuticals delivered signs of activity, though the former was marred by patient deaths. Subsequently Pfizer discontinued PF-07062119, though this was a GUCY2C-targeting T-cell engager.

OncologyPipeline identifies seven other anti-GUCY2C Car-T therapies in development, the most important of which is perhaps Legend’s LCAR-G08T.

Clinical-stage anti-GUCY2C Car-T therapies

Source: OncologyPipeline.